Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

15.7 The Suicide Gene Strategy
sing immune reconstitution after T-depleted transplants, i. e. antitumor (GvL) and alloreactive
(GvHD) responses; the GCV sensitivity of transduced cells was assessed in
vivo. Patients surviving less than 30 days after lymphocyte infusion were excluded
from response analysis; patients surviving less than 90 days after infusion were excluded
from GvHD analysis.
Thirty-three patients were enrolled in the study, 24 were been infused and 16 were
evaluable for response. Eight patients were not evaluable because of early death after
infusion.
The clinical results obtained in the evaluable patients of the Treatment protocol are
summarized in Tab. 15.6. The clinical responses were directly associated with survival
and in vivo expansion of transduced lymphocytes. GvHD followed transduced cell
infusions in three out of 16 patients evaluable for this complication. The in vivo efficacy
of the suicide system was evaluable in five patients. GCV was administered for
GvHD in three patients and resulted in complete clinical remission of GvHD signs
in two cases; in one patient with chronic extensive GvHD, an amelioration of lung
and skin signs was registered, but a complete elimination of transduced lymphocytes
could not be obtained despite extended GCV treatment. The in vivo administration of
GCV has been required as a protocol violation for cytomegalovirus (CMV) infectionunresponsive
to foscarnet in two patients treated with SFCMM-3-transduced donor
lymphocytes. In both patients, the selective elimination of transduced cells was documented
within a few days from the first GCV administration, when HSV-tk cells
dropped from 10 ±3 to levels undetectable by polymerase chain reaction (below 10 ±4 ).
The major side effect of the strategy was the development of an immunization
against the transduced cells in six out of 15 evaluable patients that resulted in complete
disappearance of cells from circulation. In these patients, an immune response
against HSV-tk/Neo fusion protein (SFCMM-2) or HSV-tk (SFCMM-3) was documented;
no immunity to the cell surface marker DNGFR was detected in any patient.
The clinical outcome of patients after immune elimination of HSV-tk cells has
been analyzed. The two patients who achieved a complete tumor remission after
HSV-tk lymphocytes infusions maintained the state of long-lasting remission after
immunization. On the contrary, the two patients who were in partial remission at
the moment of immune elimination of transduced cells had a disease relapse. In
one patient with CML, a complete cytogenetic remission was stabilized after a second
unmanipulated DLI. No local or systemic toxicity related to the gene transfer
Tab. 15.6 Antileukemia effect of HSV-tk engineered donor lymphocytes after allogeneic SCTat San
Raffaele Scientific Institute
Diagnosis Studied Evaluable CR Partial remission
CML/chronic myelomonocytic leukemia 5 5 2 2
AML 8 3 1 1
ALL 1 1 0 0
Non-Hodgkin's lymphoma 5 4 2 1
Hodgkin's disease 2 1 0 0
Multiple myeloma 2 2 1 1
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